Among infectious diseases, malaria is common in many parts of the world. Standard alkaloids such as quinine and chloroquine are becoming less and less effective because malaria parasites are developing resistance to such drugs. There is a critical and urgent need, therefore, for development of antimalarial vaccines and new antimalarial non-alkaloidal drugs to treat this increasingly widespread international health problem. With limited and now used-up funding from Johns Hopkins, we have designed, prepared, and had tested various simple structural analogs of the clinically used Chinese 1,2,4-trioxane drug artemisinin (qinghaosu). Two of our easily prepared trioxanes have been shown in vitro and very recently also in vivo (rodents and simians) to be faster than arteether in clearing parasitemia. We have also probed into the molecular mechanism of action of this relatively new class of antimalarial trioxane drugs; such mechanistic studies have enabled us to discover that carbon-centered radical intermediates are likely for the antimalarial activity of such trioxanes. We propose here to use this new understanding of molecular mechanism of action to design, prepare and have evaluated structurally modified trioxanes in which carbon-centered radical intermediates will be stabilized, leading to higher antimalarial activity. We propose also to prepare second-generation drugs improving on the best of our trioxanes (i.e. benzyl ethers and phosphate ethers) by incorporating a pharmacologically beneficial fluorine atom or a basic nitrogen atom that can be quaternized to form a water-soluble and therefore faster acting ammonium salt. Studies will include also radiolabeled trioxanes as well as hemin-trioxane adducts. This research program is likely to produce significant and practical new trioxane drugs for effective chemotherapy of malaria. A more speculative and therefore more risky aspect of this proposal addresses malaria chemoprevention by breaking the cycle of malaria transmission via the anticipated Plasmodium gametocytocidal activity of our trioxanes, in analogy with artemisinin. As medicinal chemists, we are in a unique position to make fundamental advances in molecular parasitology specifically concerning mechanism of action and improved therapeutic aspects of easily prepared and relatively inexpensive new trioxane drugs.